The actions of extracellular nucleotides in cell signaling are mediated by two classes of cell surface purinergic receptors: P2X receptors are ligand-gated ion channels activated by extracellular ATP, and P2Y receptors are G protein-coupled receptors activated by both adenine and uracil nucleotides. In the heart, for example, a variety of P2 receptors are expressed.
Cardiac P2X receptors represent a novel and potentially important therapeutic target for the treatment of heart failure. A P2X receptor on the cardiomyocyte mediates cardioprotection and is activated by ATP or its potent analogue 2-MeSATP 1, as demonstrated using the calsequestrin (CSQ) model of cardiomyopathy. Extracellular ATP can cause an ionic current in murine, rat, and guinea pig cardiac ventricular myocytes. The P2X4 receptor is an important subunit of the native cardiac P2X receptor, which mediates ionic current induced by extracellular ATP. This P2X current was up-regulated in cardiac ventricular myocytes of the CSQ hearts. Furthermore, cardiac myocyte-specific overexpression of the P2X4 receptor can mimic the beneficial effects following chronic infusion of P2X agonist analogues. This analysis suggested that regulation of this cardiac P2X receptor is protective in cardiac hypertrophy or failure.
(1′S,2′R,3′S,4′R,5′S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol, (MRS2339, 3) is an (N)-methanocarba monophosphate derivative of 2-chloro-AMP 2 that contains a rigid bicyclic ring system (bicyclo[3.1.0]hexane) in place of ribose. This ring system impedes hydrolysis of the 5′-phosphate in a model compound by its nucleotidase. Compound 3 induced a current in the CSQ myocyte similar to that by compound 1, characteristic of the action of the P2X4 receptor. Chronically administered MRS2339 (compound 3) rescued the hypertrophic and heart failure phenotype in the CSQ-overexpressing mouse. When administered via an Alzet mini-osmotic pump, it significantly increased longevity as compared to vehicle-injected mice. The improvement in survival was associated with decreases in heart weight/body weight ratio and in cross-section area of the cardiac myocytes. Compound 3 was devoid of any vasodilator action in aorta ring preparations indicating that its salutary effect in heart failure was not due to any vascular unloading.
Activation of this myocyte P2X receptor leads to the opening of a nonselective cation channel permeable to Na+, K+, and Ca2+. The current is inward at negative membrane potentials, reverses near 0 mV, and becomes outward at positive potentials. The continuous activation of this receptor channel under the resting or negative membrane potentials would produce an inward current while its activation during depolarized portions of the action potential should lead to an outward current. These ionic currents represent a possible ionic mechanism by which the cardiomyocyte P2X channel achieves its protective effect.
What is needed are additional myocyte P2X receptor activators that have cardioprotection activity.